The measurement of serum prostate specific antigen (PSA) is widely used for the screening and early detection of prostate cancer1-3. Serum PSA that is measurable by current clinical immunoassays exists primarily as either the free “non-complexed” form (free PSA), or as a complex with α1-antichymotrypsin (ACT)4,5. The ratio of free to total PSA in serum has been demonstrated to significantly improve the discrimination of PCa from benign prostatic diseases, with higher ratios correlating with a lower risk of prostate cancer6,7. While benign prostate hyperplasia (BPH) is the most common benign prostatic disease it is recognized that other benign diseases such as prostatitis, prostatic infarct and prostatic injury can also elevate serum PSA and cause changes in the free to total PSA ratio.
The biological mechanism for the variable levels of free PSA in serum is unknown. The serum PSA that has become complexed is likely to be relatively homogeneous since this represents enzymatically active, intact PSA. The PSA released from the PSA-ACT complex in prostate cancer (Pca) and benign prostate hyperplasia (BPH) serum was found to be indistinguishable from seminal plasma PSA, which confirms this assumptions8. It follows that free PSA may offer better biochemical insight, and that a characterization of the molecular forms of free PSA could help elucidate their prostatic origin and mechanism of release into the serum. However, attempts to purify and characterize the low levels of PSA from serum in the diagnostically relevant range near 10 ng/ml have not generally been considered feasible with current technologies. So far, studies have focused primarily on serum from men with unusually high levels of PSA, with 100's or 1000's of ng/ml PSA. However, other groups have failed to identify pPSA in serum containing these high levels of PSA9,10. While studies using high serum PSA levels are suggestive, they suffer a common drawback in that this PSA may not reflect the kind or percentage of PSA that is typically present in the early stages of disease, where PSA is 10 ng/ml or less. PSA released from large primary tumor lesions or metastatic disease may have different biochemical properties than PSA released from early, possibly lower grade disease. Therefore, in order to be useful for clinical detection of early prostate cancer, the truncated pPSA forms would have to be present at significant levels in serum with diagnostically relevant levels of total PSA near 10 ng/ml.
Accordingly, a need exists to characterize different forms of free PSA present in prostate cancer serum with diagnostically relevant levels of total PSA near 10 ng/ml. A need also exists to determine the diagnostic potential of these pPSA forms in prostate cancer detection. In addition, since any characterization of the free PSA forms in serum must necessarily depend on the development of mAbs, a need also exists for developing antibodies that are specific for these pPSA forms.